Ablation of Ghrelin O-Acyltransferase Does Not Improve Glucose Intolerance or Body Adiposity in Mice on a Leptin-Deficient ob/ob Background

Henriette Kirchner,Paul T Pfluger,Dhiraj Kabra,Jenna Holland,Matthias H Tschöp,Kristy M Heppner,Kathrin Maedler

doi:10.1371/journal.pone.0061822

Henriette Kirchner, Paul T Pfluger + Show 5 more

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https://doi.org/10.1371/journal.pone.0061822

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Abstract

Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two ghrelin isoforms acyl- and desacyl ghrelin in regulating glucose homeostasis. Therefore ghrelin activating enzyme Ghrelin-O-acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl ghrelin deficiency or desacyl ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl ghrelin nor the increased ratio of desacyl/acyl ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency.

Highlights

Diabetes is one of the major public health burdens affecting industrialized nations and based on current estimates it will become an even larger problem in the future
The gastrointestinal hormone ghrelin is an endogenous regulator of energy homeostasis that potently increases food intake and body adiposity
It may function as a direct regulator of glucose metabolism as ghrelin has been suggested to have paracrine or autocrine effects on the pancreas, thereby contributing to the regulation of insulin secretion [17]

Summary

Introduction

Diabetes is one of the major public health burdens affecting industrialized nations and based on current estimates it will become an even larger problem in the future. A stomach hormone linked to body weight regulation and obesity, has recently been suggested to be such a key regulator of glucose metabolism [2,3,4,5,6]. Endogenous ghrelin exists in two principal forms, as a pure 28amino acid peptide (desacyl ghrelin) and as an acylated peptide (acyl ghrelin) that carries a fatty acid side chain. Two reports on transgenic desacyl ghrelin overexpressing mice suggest a role for desacyl ghrelin in the regulation of body weight, either by reducing growth [12] or by impairing white adipose tissue development [6]. While the role of acyl ghrelin on food intake and body adiposity is well established, a potential impact of desacyl ghrelin on body weight control remains largely uncertain

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